This invention relates to microspheres. More particularly it relates to processes for the preparation of microspheres of a polymer and a core material and to products produced thereby. In one particular aspect it relates to processes for the preparation of microspheres of a polymer and a drug and to products produced thereby.
Broadly, the microspheres of this invention may be described as: microcapsules of a core material, e.g., drug, and a polymer wherein the polymer coats a drug particle; or microprills which are homogeneous mixtures of a core material, e.g., drug and a polymer. The processes of this invention are directed to the preparation of microspheres by the novel use of carboxylic acid salt surfactants as emulsifiers in oil-in-water emulsions which utilize solvent removal techniques to isolate the discrete microspheres.
Microencapsulation processes based on solvent removal from emulsions are known in the prior art and have been reviewed in various publications. These include: M. Morishita et al in "Microencapsulation: Processes and Applications," edited by J. E. Vandegaer, Plenum Press, N.Y., 1974, pp. 115-116; A. Watanabe and T. Hayashi in "Microencapsulation," edited by J. R. Nixon, Marcel Dekker, Inc., N.Y., 1976, pp. 18-19; A. Kondo, "Microcapsule Processing and Technology," edited and revised by J. W. Van Valkenburg from the original 1970 Japanese edition, Marcel Dekker, Inc., N.Y., 1979, pp. 106-120.
The basis of the prior art processes involves dissolving or dispersing the core material in a solution of the wall-forming material dissolved in a volatile, water-immiscible organic solvent. The organic phase is emulsified with an aqueous solution containing a surface active agent to form a dispersion of oil droplets which would yield microspheres upon removal of the organic solvent by evaporation (distillation or spray-drying), solvent extraction or freeze-drying. However, the products from these processes are agglomerated microspheres and not discrete particles, suitable for example, in parenteral applications.
Solvent removal from an emulsion is disclosed in U.S. Pat. Nos. 3,523,906 and 3,523,907 wherein an aqueous solution as core material was encapsulated by the emulsion method using a hydrophilic colloid such as gelatin or polyvinyl alcohol as the emulsifier.
The use of the emulsion process for microencapsulation of medicaments is described in U.S. Pat. No. 3,960,757 wherein a hydrophilic colloid (e.g., gelatin, polyvinyl alcohol) and/or a surface active agent (anionic or nonionic type having an HLB of not less than 10) is used as the emulsifier.
A mixed gelatin-nonionic surface active agent system in a similar process for preparing beads of biodegradable polymer e.g., polylactic acid containing progesterone was used by S. Yolles et al in "Controlled Release Polymeric Formulations," edited by D. R. Paul and F. W. Harris, American Chemical Society, Washington, D.C., 1976, pp. 124-125. The microspheres formed were 250-420 micron diameter with some agglomerates present.
An anionic surfactant, sodium dodecyl sulfate, utilizing the emulsion process to encapsulate pesticides with polylactic acid is described by H. Jaffe in U.S. patent application Ser. No. 943,940 (filed Aug. 17, 1978). The product was a coarse powder of large aggregates of microspheres, most of which were 177-595 microns.
U.S. Pat. No. 3,660,304 discloses a method for producing oily liquid-containing microcapsules using a mixture of high and low boiling point solvents, in an oil-in-water emulsion system. There is no distinction or appreciation of the differences in performance between the many classes of surface active agents in the encapsulation process. Fatty acid salts are mentioned among the many surface active agents disclosed.
Polyvinyl alcohol was employed as the emulsifier in a solvent evaporation process for obtaining microspheres of polylactic acid by L. R. Beck et al, "A New Long-Acting Injectable Microcapsule System for the Administration of Progesterone," Fertility and Sterility 31:5, 545-551 (1979). The microspheres were 10-250 microns and were free of agglomerates.
Using biodegradable polymers such as polylactic acid as the wall-forming material in microspheres for injectable application eliminates the need for surgical removal of the microspheres after delivery of the drug. For controlled release of drug suitable for parenteral administration, the microspheres should be free of agglomerates and the size should be large enough to provide adequate duration of release yet small enough not to restrict passage through the standard syringe needles. Thus, the maximum size would be about 150 microns for a conventional No. 20 gauge needle. Except when polyvinyl alcohol was employed as the emulsifier, agglomerates were reported to be present and the 150 micron size limitation was greatly exceeded in the above prior art references preparing microspheres with polylactic acid.
However, polyvinyl alcohol is listed in the 1976 Registry of Toxic Effects of Chemical Substances. It has been implicated as being carcinogenic when introduced parenterally into animals, according to W. C. Hueper, "Carcinogenic Studies on Water-Soluble and Insoluble Macromolecules," Archives of Pathology, 67, 589-617 (1959). Residual amounts of occluded polyvinyl alcohol in the microspheres due to the interfacial property of emulsifier would be undesirable for injectable pharmaceutical application.
Thus, there is no satisfactory emulsifier reported in the prior art for microencapsulation processes based on solvent removal from aqueous emulsions, which produce discrete, non-agglomerated microspheres suitable both for pharmaceutical and non-pharmaceutical applications.